Abstract Thehumanbodyisacomplexmachinethatisconstructedthroughtightlyorchestratedpatternsofgeneexpression during embryonic and postnatal development. Changes in how genes are regulated during development are thoughttobeamajorsubstratefornaturalselectionandhavelikelycontributedtotheevolutionofthehumanform. While changes in gene regulation might have contributed to sculpting of human specific features of our limbs and brains,thesamemoleculareventsdrivingthesechangescanhavedeleteriousconsequenceswhenacriticalgene orregulatorysequenceisaffected.Ifthesemolecularchangescauseperturbedgeneregulationduringembryonic development the resulting child can have birth defects such as congenital heart defects, orofacial clefting, or neurological dysfunction. In cases where a birth defect is not observed the individual may be instead be predisposedtovariousdiseaseslaterinlifeincludingautism,diabetes,orcancer.Whileourunderstandingofthe genetic code for protein coding genes allows us to make predictions about disease risk or identify the most likely causeofadisease,ourlimitedunderstandingoftheinformationencodedintherestofourgenomepreventssuch predictionsandcausativeassignments.Theadventofinexpensivewholegenomesequencingispoisedtochange the way the field of medicine operates, however our lack of understanding of large expanses of our genome prevents us from providing the promise of personalized genomic medicine. Efforts to identify gene regulatory sequences must be expanded to many stages and tissues of human development to fully decipher this code. Perhapsmoredauntingapropositionisalsoidentifyingwhenandwherearegulatorysequencetargetsageneand how sequence changes affect gene regulation. Here we propose to address many of these problems through applicationoffunctionalgenomicstechniquesdirectlyinembryonictissuesofhumanandrodents.Wewillcreatea comprehensivecatalogofgeneregulatorysequencesthatareactiveveryearlyinembryonicdevelopment,identify the genes that they target, and begin to dissect their regulatory capacities. These datasets and analyses will establish the foundation upon which we can better interpret our genomes to improve future human health and preventdisease.